Over one million women worldwide are diagnosed with breast cancer each year. Roughly 20% of all breast cancers overexpress the human epidennal growth receptor 2 (HER2-positive subtype). HER2-targeted therapies, including Herceptin and lapatinib, account for 55% of the breast cancer therapy market in 2011 (or $5 billion annually). Response to HER2-targeted therapies typically average about one year due to developed resistance. This represents an area of unmet clinical need. HER2 over-expression has been clearly linked to aggressive and abnonnal tumor growth, rapid metastases, and drug resistance in this cancer subtype. siRNA for knocking down HER2 offers a new treatment modality to overcome drug resistance. We are developing a novel nanoparticle platform for therapeutic siRNA delivery. Novelty lies in the hybrid polymeric-inorganic nanoparticles that take full advantage of both classes of materials to overcome siRNA delivery barriers (e.g., poor bioavailability, poor cellular uptake, and off-target effects) and enable large-scale manufacturing of the nanocontruct. This Phase I portion will optimize the nanoparticle platforms to achieve >70% knockdown ofHER2 in three HER2-positive breast cancer cell lines, leading to programmed death of the cancer cells, while having no adverse effect on HER2-negative cells or nonnal cells. The most optimized nanoparticle platform will undergo further in vivo evaluation in Phase II SBIR project.